ABSTRACT Retinopathy of Prematurity (ROP) is a potentially blinding disease that occurs in the earliest weeks of life. The disease is currently one of the top three causes of childhood blindness in the world and is the number one cause of blindness in countries of a medium level of economic development. One in nine children born in the US, or half a million babies per year, are born prematurely; worldwide, the number is estimated at 15 million. Current American Academy of Pediatrics guidelines mandate an ophthalmology screening exam for 2-5% of these infants to assess the risk of developing ROP. Ophthalmologists diagnose and make decisions about the initial treatment of ROP based on the appearance of the retinal blood vessels. The current standard of care for diagnosis of ROP is a subjective evaluation of vessel dilatation and tortuosity based on a static fundus photograph. The only instruments marketed for imaging the infant retina that may assist in ROP diagnostics are bulky and expensive making them unsuitable for widespread use. Hence, there is a critical need for a standardized, more accurate method of screening infants for ROP using a convenient, affordable, and portable instrument. Semi-automated methods are available to quantify the vascular morphologic changes seen in ROP; however, these technologies lack the ability to objectively and automatically quantify and detect the condition. This Phase I effort proposes to design and develop the XyCAM NEO??a handheld, noninvasive imager capable of measuring retinal blood flow with high spatial resolution, for diagnosis and management of ROP and test the crucial hypothesis that XyCAM NEO derived flow-based metrics can be utilized for monitoring of status of ROP and Plus Disease. The XyCAM NEO will use laser speckle contrast imaging (LSCI) to capture blood flow information without the need for exogenous dyes. This additional information is complementary to that available using fundus photography, and the addition of novel flow-based biomarkers to conventional biomarkers such as vessel tortuosities, diameters, lengths, and densities is expected to improve diagnostics. Specifically, we propose to adapt our retinal imaging technology that has been validated in adult human subjects for use in premature infants in the neonatal intensive care unit (NICU) environment; and demonstrate through an early feasibility clinical study that blood flow in premature infants with severe ROP is different than in those with low-grade ROP. In doing so, we also expect to demonstrate the ability and potential of the XyCAM NEO derived flow-based biomarkers to discriminate between a severe and mild disease state. If successful, we anticipate undertaking a Phase II project to conduct a rigorous clinical study to statistically evaluate, in a large number of subjects, the ability of the XyCAM NEO to identify ROP based on the metrics identified in the feasibility study (i.e., characterize the diagnostic sensitivity and specificity) and compare the results with those obtained using current practice standards. We will investigate the suitability of flow-based assessment for characterizing the short- and long-term response to various ROP treatment options, thereby permitting greater optimization of therapy. The results of this work will facilitate marketing of a paradigm shifting medical device for timely diagnosis of a condition that impacts all aspects of a child's development and shapes the adult they become.